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Ref Type Journal Article
PMID (23908597)
Authors Byron SA, Chen H, Wortmann A, Loch D, Gartside MG, Dehkhoda F, Blais SP, Neubert TA, Mohammadi M, Pollock PM
Title The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Neoplasia (New York, N.Y.) 15 8 2013 Aug 975-88 Neoplasia
URL
Abstract Text We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified 14 dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2(mutant) endometrial cancers (ECs). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors, whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2(mutant) cell lines, three of seven showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2(N550K) in JHUEM-2 cells (FGFR2(C383R)) conferred resistance (about five-fold) to PD173074, providing independent data that FGFR2(N550K) can be associated with drug resistance. Biochemical in vitro kinase analyses also show that ponatinib is more effective than dovitinib at inhibiting FGFR2(N550K). We propose that tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 E566G missense gain of function FGFR2 E566G (corresponds to E565G in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). E566G results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). Y
FGFR2 I548V missense gain of function FGFR2 I548V lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). I548V confers a gain of function on the Fgfr2 protein, as demonstrated by increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in cell culture (PMID: 23908597).
FGFR2 K641N missense gain of function FGFR2 K641N lies within the protein kinase domain of the Fgfr2b protein (UniProt.org). K641N (reported as K642N) results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597).
FGFR2 L618M missense gain of function FGFR2 L618M (corresponds to L617M in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L618M results in increased Fgfr2 kinase activity, enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597), and elevated kinase activity compared to wild-type Fgfr2 protein in substrate phosphorylation assays (PMID: 28166054).
FGFR2 M536I missense gain of function FGFR2 M536I (corresponds to M535I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M536I results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597).
FGFR2 M538I missense gain of function FGFR2 M538I (corresponds to M537I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M538I confers a gain of function to the Fgfr2 protein as demonstrated by increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in cell culture (PMID: 23908597), and has been associated with decreased sensitivity to some FGFR inhibitors (PMID: 23908597).
FGFR2 N550H missense gain of function FGFR2 N550H (corresponds to N549H in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550H results in increased Fgfr2 kinase activity, as well as increased Fgfr2 phosphorylation and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). Y
FGFR2 N550K missense gain of function FGFR2 N550K (corresponds to N549K in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550K results in increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597).
FGFR2 N550S missense gain of function FGFR2 N550S lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550S results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597).
FGFR2 N550T missense gain of function FGFR2 N550T (corresponds to N549T in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550T results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597).
FGFR2 V565I missense gain of function FGFR2 V565I (corresponds to V564I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565I results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 C383R FGFR2 N550K endometrial cancer resistant PD173074 Preclinical Actionable In a preclinical study, an endometrial cancer cell line harboring FGFR2 C383R and expressing FGFR2 N550K demonstrated resistance when treated with PD173074 (PMID: 23908597). 23908597
FGFR2 M538I Advanced Solid Tumor decreased response Ponatinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with Iclusig (ponatinib) (PMID: 23908597). 23908597
FGFR2 K660E Advanced Solid Tumor resistant Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 K660E were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 S252W Advanced Solid Tumor conflicting Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 S252W were sensitive to Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 I548V Advanced Solid Tumor decreased response Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 I548V demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 E566G Advanced Solid Tumor resistant Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 E566G were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 N550S Advanced Solid Tumor decreased response PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 N550S demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 N550H Advanced Solid Tumor decreased response Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 N550H demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 I548V Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 I548V (PMID: 23908597). 23908597
FGFR2 K660E Advanced Solid Tumor decreased response PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 K660E demonstrated a decreased response when treated with PD173074 (PMID: 23908597). 23908597
FGFR2 E566G Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 E566G (PMID: 23908597). 23908597
FGFR2 V565I Advanced Solid Tumor resistant Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 V565I were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 N550K Advanced Solid Tumor resistant Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 N550K were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 I548V Advanced Solid Tumor decreased response PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 I548V demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 V565I Advanced Solid Tumor resistant PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 V565I were resistant to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 N550S Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 N550S (PMID: 23908597). 23908597
FGFR2 N550K Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 N550K (PMID: 23908597). 23908597
FGFR2 N550H Advanced Solid Tumor resistant PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 N550H were resistant to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 M538I Advanced Solid Tumor decreased response Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 N550H Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 N550H (PMID: 23908597). 23908597
FGFR2 N550S Advanced Solid Tumor decreased response Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 N550S demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 N550K Advanced Solid Tumor resistant PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 N550K were resistant to PD173074 (PMID: 23908597). 23908597
FGFR2 L618M Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 L618M were sensitive to treatment with Iclusig (ponatinib) (PMID: 23908597). 23908597
FGFR2 V565I Advanced Solid Tumor resistant Ponatinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 V565I were resistant to treatment with Iclusig (ponatinib) (PMID: 23908597). 23908597
FGFR2 L618M Advanced Solid Tumor decreased response Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 L618M demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 M536I Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 M536I (PMID: 23908597). 23908597
FGFR2 M536I Advanced Solid Tumor decreased response Dovitinib Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 M536I demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). 23908597
FGFR2 M536I Advanced Solid Tumor decreased response PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 M536I demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 M538I Advanced Solid Tumor decreased response PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 E566G Advanced Solid Tumor resistant PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 E566G were resistant to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 L618M Advanced Solid Tumor decreased response PD173074 Preclinical Actionable In a preclinical study, transformed cells expressing FGFR2 L618M demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). 23908597
FGFR2 K660E Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23908597). 23908597